Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
Weill Cornell Medical College, New York, New York.
Blood Cancer Discov. 2023 May 1;4(3):208-227. doi: 10.1158/2643-3230.BCD-22-0128.
The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL. We identified alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex structural variants including chromothripsis. We found that high ploidy in cHL is often acquired through multiple, independent chromosomal gains events including whole-genome duplication. Evolutionary timing analyses revealed that structural variants enriched for RAG motifs, driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID-driven mutagenesis usually preceded large chromosomal gains. This study provides a temporal reconstruction of cHL pathogenesis.
Previous studies in cHL were limited to coding sequences and therefore not able to comprehensively decipher the tumor complexity. Here, leveraging cHL whole-genome characterization, we identify driver events and reconstruct the tumor evolution, finding that structural variants, driver mutations, and AID mutagenesis precede chromosomal gains. This article is highlighted in the In This Issue feature, p. 171.
经典霍奇金淋巴瘤（cHL）中恶性霍奇金和里德-斯特恩伯格（HRS）细胞的罕见性限制了对 cHL 基因组学的研究能力。为了解决这个问题，我们的小组之前已经优化了荧光激活细胞分选技术来纯化 HRS 细胞。使用这种方法，我们现在报告了 HRS 细胞的全基因组测序图谱，并重建了导致 cHL 的致病事件的时间顺序和可能病因。我们确定了以前在 cHL 中未描述的驱动基因改变、APOBEC 突变活性以及包括染色体重排在内的复杂结构变体的存在。我们发现，cHL 中的高倍体通常是通过包括全基因组复制在内的多个独立的染色体增益事件获得的。进化时间分析表明，富含 RAG 基序的结构变体、B2M、BCL7A、GNA13 和 PTPN1 中的驱动突变以及 AID 驱动的诱变的开始通常先于大的染色体增益。这项研究提供了 cHL 发病机制的时间重建。
以前在 cHL 中的研究仅限于编码序列，因此无法全面破译肿瘤的复杂性。在这里，利用 cHL 全基因组特征，我们确定了驱动事件并重建了肿瘤的进化，发现结构变体、驱动突变和 AID 诱变发生在染色体增益之前。本文在本期的特色文章中进行了重点介绍，第 171 页。
